Neuroradiology (2014) 56:41–50 DOI 10.1007/s00234-013-1303-1
INTERVENTIONAL NEURORADIOLOGY
Clinical significance of post-interventional cerebral hyperdensities after endovascular mechanical thrombectomy in acute ischaemic stroke Omid Nikoubashman & Arno Reich & Mirco Gindullis & Katharina Frohnhofen & Rastislav Pjontek & Marc-Alexander Brockmann & Jörg B. Schulz & Martin Wiesmann
Received: 2 July 2013 / Accepted: 4 November 2013 / Published online: 5 December 2013 # Springer-Verlag Berlin Heidelberg 2013
Abstract Introduction This study aims to investigate the clinical significance of post-interventional cerebral hyperdensities (PCHD) after endovascular mechanical thrombectomy in acute ischaemic stroke. Methods Data of 102 consecutive patients who received postinterventional CT scans within 4.5 h after mechanical thrombectomy were analysed retrospectively. Results Sixty-two of 102 patients (60.8 %) had PCHD on their post-interventional CT scans. The most common site of PCHD was the basal ganglia. PCHD were persisting in 13 of 62 patients (21.0 %), and transient in the remaining 49 patients (79.0 %) within 24 h. Four patients with PCHD and four patients without PCHD suffered from parenchymal haemorrhage. Neither ASA nor Clopidogrel, Tirofiban or rtPA were risk factors for PCHD. Final infarction size was congruent with or bigger than areas of PCHD in 93.3 % of cases in our series. Conclusion PCHD was not a risk factor for parenchymal haemorrhage in our series. The occurrence of PCHD was strongly related to the prior presence of infarction. PCHD was also a strong predictor for final infarction size. Keywords Stroke . Post-interventional CT . Hyperdensity . Haemorrhage . Mechanical recanalisation Electronic supplementary material The online version of this article (doi:10.1007/s00234-013-1303-1) contains supplementary material, which is available to authorized users. O. Nikoubashman : K. Frohnhofen : R. Pjontek : M.2/3 of the vessel territory) [11]. Statistical analyses We applied Chi2 tests, Fisher's exact tests and t tests where adequate. Logistic regression analyses were performed for complex correlations. Results with a p value under 0.05 were considered significant. All statistical analyses were performed using SPSS® 20 software (IBM®, San Jose, California, USA).
Transient PCHD PCHD that became iso- or hypodense to the unaffected contralateral hemisphere within 24 h. Persisting PCHD PCHD that remained hyperdense during at least 24 h. Haemorrhage (according to the ECASS 1 and 2 definition): – – – –
– –
PH: Parenchymal haemorrhage (coagulum) with mass effect PH1: Less that 30 % of the infarcted area with mild spaceoccupying effect PH2: Greater than 30 % of the infarcted area with significant space-occupying effect HI: Haemorrhagic infarction: petechial infarction without space-occupying effect; non-solid and without spaceoccupying effect, respecting borders of grey and white matter [12]. HI1: Small petechiae HI2: More confluent petechiae
Early HI occurring within 36 h after recanalisation was distinguished from delayed HI occurring 36 h after recanalisation [13]. Infarction Infarction diagnosis was based on MRI via diffusion weighted imaging including ADC maps in combination with T2-FLAIR sequences whenever possible. Infarction diagnosis via CT was complicated when final infarction size
Neuroradiology (2014) 56:41–50
could not be assessed in the presence of persisting hyperdensities. We supposed that a complete infarct demarcation can be expected in the following settings: (1) patients without PCHD—CT scan performed at least 12 h after recanalisation; (2) patients with PCHD—CT scan performed at least 12 h after recanalisation if all former hyperdense areas are hypodense. Since it is unknown yet to which extent PCHD correspond to parenchymal infarction, final infarction size was not assessed if PCHD remained isodense to normal parenchyma in follow-up CT scans performed within 24 h after recanalisation. Final infarct size was also not assessed, when PCHD remained hyperdense in the last follow-up CT.
Results Patients One hundred two patients were analysed (49 women, 53 men, n. s.). Mean age of patients was 70.3 years (SD 17.1 years). Men were significantly younger than women (67.8 versus 74.3 years, p =0.036). Interventional treatment Details on interventional treatments are presented in Table 2. Clinical findings Initial median mRS and NIHSS scores of all patients were 5.0 and 14.5, respectively. The mRS score at discharge and the mRS score at 3 months were 4.5 and 4.0, respectively. There was no significant difference between the mRS scores of patients with and without PCHD (administration: p =0.520, discharge: p =0.463, 3 months: p =0.382, twotailed Student's t test).
43
Radiological findings PCHD Sixty-two of 102 patients (60.8 %) had PCHD on their postinterventional CT scans. However, we found PCHD in only 22 of 72 patients (31 %) when we considered only the latest CT performed within 24 h after recanalisation. All visually distinctive hyperdense areas had an increased density of at least 5 HUmax compared to the unaffected contralateral hemisphere and were therefore included in this study. Overall, there were 744 ASPECTS areas in 62 patients. PCHD was present in 206 of 744 ASPECTS areas (27.7 %). Localisations of PCHD were the following (according to ASPECTS): lentiform nucleus (in n = 50 of 62 cases, 80.6 %), M2 area (n =30, 48.4 %), insula (n =30, 48.4 %), caudate nucleus (n =29, 46.8 %), M5 area (n =19, 30.6 %), M1 area (n =11, 17.7 %), M4 area (n =10, 16.1 %), M3 area (n =9, 14.5 %), M6 area (n =8, 12.9 %), A area (n =6, 9.7 %), internal capsule (n =4, 6.5 %). One patient with a foetal posterior cerebral artery had PCHD in the P area. PCHD were persisting in 13 of 62 patients (21.0 %), and transient in the remaining 49 patients (79.0 %) within 24 h. Mean HUmax of all hyperdense areas was 83.7 HU (median, 77.0; ranging from 58 to 152 HU; SD, 22.5). Mean HUmax of areas corresponding to transient hyperdensities was 79.2 HU (median, 74; ranging from 61 to 152 HU; SD, 19.8) and 87.8 HU for areas corresponding to persisting hyperdensities (median, 80; ranging from 72 to 142; SD,19.6). This difference was not statistically significant (p = 0.217, Student's t test). Furthermore, mean HUmax of hyperdense areas of patients with parenchymal haemorrhage was not significantly different from those of patients without parenchymal haemorrhage (p =0.476, Student's t test). Characteristics of patients with and without PCHD are provided in Table 3.
Procedural parameters Haemorrhage Mean time between onset of symptoms until recanalisation or discontinuation of therapy was 325.2 min (median, 303.0; ranging from 120 to 813 min; SD, 134.2). Mean duration of neuroradiological procedure was 131.0 min (median, 115.0; ranging from 30 to 351 min; SD, 74.7). Mean time between recanalisation or discontinuation of therapy until postinterventional CT scan was 76.6 min (median, 70.0; ranging from 27 to 250 min; SD, 34.2). An average of 2.5 recanalisation attempts per patient were performed (median, 2.0; ranging from 1 to 8; SD, 1.7). Recanalisation was successful after one single pass in 39 cases (38.2 %). Stenting of the internal carotid artery was necessary in 23 cases (22.5 %). One stent was placed in the M1 segment of the middle cerebral artery.
Depending on availability of follow-up studies, the occurrence of haemorrhage could be assessed in 88 of 102 patients. This comprises 48 patients with PCHD and 40 patients without PCHD. Parenchymal haemorrhage Four of 88 patients (4 %) suffered from parenchymal haemorrhage with a space occupying effect (ECASS PH2). All four haemorrhagic events occurred within 1 to 4 days after recanalisation. One of these four patients had PCHD (Fig. 1). There was symptomatic mass haemorrhage in two of these four cases—including one patient with PCHD. Haemorrhage in this latter patient occurred 1 day after recanalisation, involved the hyperdense area and was lethal.
44
Neuroradiology (2014) 56:41–50
Four additional patients (4 %) had smaller asymptomatic parenchymal haemorrhage (ECASS PH1) within 4 days after recanalisation. Three of these four patients had PCHD (Fig. 2). PH1 haemorrhage involved hyperdense areas in all 3 patients with PCHD. An overview of all eight patients with PH is provided in Table 4.
Follow-up imaging of these 84 patients was performed after a mean period of 4.2 days after recanalisation (median, 2.2; ranging from 7.0 h to 28.9 days; SD, 4.9 days). Infarct size was assessed via CT in 58 cases (69.0 %) and MRI in 26 cases (31.0 %).
Haemorrhagic infarction Early haemorrhagic infarction occurring within 36 h after recanalisation was present in 2 of 88 patients (2 %). Overall, there was HI in 22 of 88 cases (25.0 %). Complete recanalisation (≥TICI 2b) was significantly associated with the occurrence of HI (p =0.047, two-sided Fisher's exact test).
Predisposing factors for the occurrence of PCHD
Infarction Follow-up imaging suitable for infarction diagnosis was available for 84 patients. This comprises 45 patients with PCHD and 39 patients without PCHD.
Basic statistics indicated that female sex, amount of contrast agent, presence of infarction on intitial CT scan and number of recanalisation attempts may be predisposing factors for the occurrence of PCHD (Table 3). However, logistic regression analyses revealed that only the presence of infarction in the initial CT scan constituted an independent predisposing factor for the occurrence of PCHD (p =0.016) whereas the influence of sex (p =0.205), the amount of contrast agent (p =0.287) and the number of recanalisation attempts (p = 0.261) did not prove significant.
Table 2 Overview of procedural parameters. Number of patients indicated if less than all Vessels
Left/right MCA Terminal ICA with bifurcation Proximal ICA into MCA Proximal ICA and MCA Proximal ICA ACA ACA and MCA Initial degree TICI 0 of occlusion TICI 1 TICI 2a TICI 2ba Final degree of TICI 0 occlusionb TICI 1
rtPA therapy
rtPA dose
TICI 2a TICI 2b TICI 2c TICI 3 Patients with rtPA regardless of application method Patients with intravenously applied rtPA bridging therapy Patients with intraarterially applied rtPA Both intravenous and intraarterial rtPA Mean cumulative rtPA dose regardless of application method Mean dose of intraarterially applied rtPA Mean dose of intravenously applied rtPA
57:45 64 23 8 1 4 1 1 97 (95.1 %) 2 (2 %) 2 (2 %) 1 (1 %) 7 (6.9 %)
(p =0.276, binomial test)
8 (7.8 %) 3 (2.9 %) 11 (10.8 %) 6 (5.9 %) 67 (65.7 %) 74 (72.5 %) 65 (63.72 %) 23 (22.5 %) 14 (13.7 %) 39.3 mg (median, 35.0; ranging from 8 to 98 mg; SD, 20.1). 21.78 mg (median, 15.0; ranging from 5 to 50 mg; SD, 14.5) 37.0 mg (median, 30; ranging from 10 to 98 mg; SD, 20.5).
ICA internal carotid artery, ACA anterior cerbral artery, MCA middle cerebral artery, rtPA recombinant tissue-type plasminogen activator a
Occlusion of the pericallosal artery with severe perfusion deficits in CT perfusion imaging
b
All TICI scores improved after treatment except for seven patients with initial and final TICI 0 occlusions (93.1 %)
Neuroradiology (2014) 56:41–50 Table 3 Overview of patients with and without post-interventional cerebral hyperdensities (PCHD)
Number of patients analysed are indicated in parentheses. p values according to Pearson's Chi2 test, Fisher's exact test and Student's t test PH parenchymal haemorrhage according to ECASS criteria (see above), HI haemorrhagic infarction according to ECASS criteria (see above), GP 2b/3a Glycoprotein 2b/3a * significant p-values
45
PCHD
No PCHD
p value
n (n) Female/male (102) Age (102) Median NIHSS score at admission Median mRS score at admission
62 (60.8 %) 35:27 71.31 years 14.5 5.0
40 (39.2 %) 14:26 70.24 years 15.0 5.0
0.037* 0.034* 0.737 0.428 0.520
Median mRS score at discharge Median mRS score at 3 months Symptom onset—recanalisation (69) Intervention duration (102) Recanalisation—post-interventional CT (102) No. of recanalisation attempts (102) Infaction in initial CT (102) Final TICI score >2a (102) Amount of contrast agent (102) i.v. rtPA (102) i.a. rtPA (102) GP 2b/3a inhibition (102) Infarction >1/3 MCA territory (84) PH (88) PH 1 PH 2 Symptomatic HI (88)
4.5 4.0 339.51 min 137.81 min 72.85 min 2.8 39/62 53/62 238.71 ml 39/62 15/62 19/62 15/45 4/48 3/4 1/4 1/1 12/48
4.5 4.0 301.58 min 115.45 min 75.25 min 2.0 14/40 31/40 206.25 ml 26/40 8/40 11/40 13/39 4/40 1/4 3/4 1/3 10/40
0.463 0.382 0.258 0.182 0.716 0.019* 0.006* 0.420 0.032* 0.830 0.621 0.734 1.000 0.536
Effects of pharmacologic treatment There was no significant correlation between PCHD, pPCHD, PH or HI and treatment with acetylsalicylic acid (ASA), Clopidogrel, recombinant tissue-type plasminogen activator (rtPA) or Tirofiban (Tables 5 and 6).
1.000
Basic statistics indicated that there seemed to be a statistical trend towards a correlation between Tirofiban and persisting PCHD (p =0.054, one-tailed Fischer's exact test). However, regression analysis (forward, stepwise) revealed that the influence of Tirofiban on persisting PCHD was not significant (p =0.421) when statistical analyses were corrected for the actual stenting procedure as a possible time-consuming cofactor (p =0.012) (Nagelkerke's Pseudo R 2 =0.127). Correlations between PCHD and haemorrhage PCHD were not correlated with the occurrence of parenchymal haemorrhage or haemorrhagic infarction (Table 4). Correlations between PCHD and early signs of infarction in initial imaging
Fig. 1 CT scans of a 85-year-old patient (case 5, Table 4) showing large areas of PCHD in the post-interventional CT scan (a), and mass haemorrhage (ECASS PH2) in the follow-up CT scan on the same day (b). Even though this example may suggest otherwise, a large extent of hyperdensities did not prove to correlate significantly with the occurrence of haemorrhage (p =0.853, Student's t test)
Of 1,224 ASPECTS areas (90.4 %) in the initial scans of all 102 patients, 1,106 were normal while infarction was visible in 118 initial ASPECTS areas (9.6 %). In the 102 post-interventional scans, PCHD was found in 70 of 118 initially infarcted ASPECTS areas (59.3 %) and in 136 of 1,106 initially normal areas (12.3 %). Thus, sensitivity and specificity of initially infarcted areas for PCHD were 34.0 and 95.3 %, respectively. The positive predictive value for
46
Neuroradiology (2014) 56:41–50
Fig. 2 Initial CT scan (a), post-interventional CT scan (b) and follow-up T2-FLAIR (c) and T2* (d) MRI in a 64-year-old woman. The initially hypodense lentiform nucleus (a: arrow) is markedly hyperdense in the
post-interventional CT scan (b: arrow). The MRI scan performed 3 days later reveals a small parenchymal haemorrhage within the lentiform nucleus (ECASS PH1) (c and d: arrow)
hypodensities to predict PCHD was 59.3 %. The correlation between initially infarcted areas and the occurrence of PCHD was significant (p 48 h) of cerebral infarction [20]. PCHD and haemorrhagic transformation share the same features as they are mostly limited to grey matter, and are not spaceoccupying. As PCHD are observed immediately after neurointerventional treatment, it appears unlikely that extravasation of blood contributes significantly to the increased density of PCHD. Nevertheless, in principle, conventional CT cannot differentiate whether the hyperdensity in suspected PCHD is caused by contrast agent or extravasated blood [21]. Some authors distinguish between transient and persisting hyperdensities and suggest that transient PCHD correspond to extravasated contrast agent that is washed out in the course of time, whereas persisting PCHD might correspond to blood in the context of petechial bleeding [3, 4, 6]. However, it is conceivable that transient PCHD may also correspond to subtle haemorrhage, when only small and rapidly reabsorbed amounts of blood pass the damaged BBB. Furthermore, it is possible that persisting PCHD correspond to contrast agent that is trapped in infarcted parenchyma and cannot be washed out. Our analysis and data in the literature lack systematic comparisons of post-interventional CT scans and MRI scans that could help distinguishing iodinated contrast agent from blood. In the end, it is important to note that PCHD, regardless of their true nature, do not resemble parenchymal haemorrhage but physiologic haemorrhagic transformation which is associated with a benign natural history [13, 22]. Predictors of PCHD In accordance with the assumed pathomechanism of PCHD as outline above, the occurrence of PCHD was correlated mainly with the presence of infarction in the initial CT scan both in our data and in the literature [5]. Even though it appears reasonable to assume that higher amounts of contrast agent, an increased duration between onset of symptoms and recanalisation, or the application of rtPA increase the likelyhood of PCHD, neither our results nor data in the literature do support this [8, 9]. Prognostic value of PCHD to predict haemorrhage The overall haemorrhage rate of 7.8 % for parenchymal haemorrhage in our series was comparable to haemorrhage rates provided in the literature [23–29].
48
Neuroradiology (2014) 56:41–50
Fig. 3 Initial CT scan (a), post-interventional CT scan (b), and follow-up T2-FLAIR MRI (c) in a 56-year-old man show matching areas of PCHD (b: arrow) and ischaemia (c: arrow) in the right caudate and lentiform nucleus
Our data and the data provided by Parilla et al. do not suggest there is an increased haemorrhage rate in mechanically treated patients with PCHD, regardless whether transient or persisting (Tables 3 and 4) [8]. Some authors have reported that persisting PCHD may be associated with an increased risk for parenchymal haemorrhage and clinical worsening [4, 6]. However, results provided by Nakano et al. as well as our data do not support this hypothesis [3]. None of the eight cases of parenchymal haemorrhage was associated with persisting PCHD. These results do conflict with analyses dealing with patients who were treated via intra-arterial thrombolytic therapy: all authors observed an increased haemorrhage risk for patients with PCHD [1–6]. In this context, results provided by Rouchaud et al., who analysed mechanically treated patients, stand out: the authors report 11 PH2 (28.9 %) and 21 PH1 (55.3 %) bleedings in 38 patients with PCHD on the one hand, and no PH2 and 2 PH1 (8.0 %) bleedings in 25 patients without PCHD. Their results
are highly significant, but it is noteworthy that the indicated overall haemorrhage rate of 53.0 % in their series is exceptionally high [8, 28, 29]. The overall number of analysed patients may still be too small for a definitive statement. Nevertheless, present data may imply that the natural history of PCHD in the context of intra-arterial thrombolysis and PCHD in the context of mechanical recanalisation differ. Present data may imply that high local concentrations of rtPA that are applied during intra-arterial thrombolytic therapy bear an additional risk for haemorrhage [8]. Correlation between PCHD and early signs of infarction in initial imaging One of the main goals of this study was to elucidate the relationship between PCHD and infarction. Yokogami et al. showed that PCHD are likely to appear in infarcted parenchyma. There was also a significant correlation between the
Fig. 4 Post-interventional CT scan (a) and follow-up diffusion-weighted MRI (b) in a 43-year-old man. Infarcted areas (b) exceed areas with PCHD (a) in this case
Neuroradiology (2014) 56:41–50
Fig. 5 Post-interventional CT scan (a) and follow-up diffusion-weighted MRI (b) in a 77-year-old woman. There is PCHD (a: arrow) without corresponding infarction (b: arrow) in the right insula and inferior frontal gyrus
presence of infarction in the initial CT scan and occurrence of PCHD in our series. More specifically, the location of initial infarction predicted the location of PCHD: Prior infarction in the basal ganglia (lentiform nucleus and caudate nucleus) and the surrounding cortex (insula and M1 area) were significantly associated with the occurrence of PCHD in these areas. This close relationship between infarction and PCHD is also expressed in an overall positive predictive value of 59.3 % for prior infarction to predict PCHD. Correlation between PCHD and final infarction in follow-up imaging The overall positive predictive value for PCHD to predict final infarction was 94.8 % in our series. Even though this figure is very high, one would expect a higher positive predictive value given the hypothesis that disruption of the BBB, thus infarction, is postulated in the presence of PCHD. Final infarct demarcation was lacking in three patients, more precisely in 7 of 134 areas with PCHD. Sulcal contrast agent mimicking parenchymal PCHD due to volume effects might be a possible explanation for the discrepancy between PCHD and infarct demarcation in two of these three patients. However, there was a clear discrepancy between PCHD and final infarction in one patient with a follow-up MRI examination (Fig. 5). This finding was unexpected given the hypothesis that disruption of the BBB is needed for the development of PCHD. A possible explanation could be a transiently increased permeability of the BBB for the contrast agent Iopamidol due to transient ischaemia [30]. In summary, an area with PCHD is most certainly infarcted. However, our data suggest that in rare cases PCHD may also occur in the context of transient ischemia. Final infarction size was congruent with, or bigger than, areas of PCHD in all but three cases (93.3 %) in our series (see above). More precisely, infarction size surpassed areas of PCHD in 57.8 % of patients (Fig. 4). The majority of PCHD
49
cases involved the basal ganglia—first and foremost the lentiform nucleus (80.6 %). Consequently, additional infarction was mainly found in additional cortical areas. Furthermore, our results imply that infarction size is likely to surpass areas of PCHD if final recanalisation is unsatisfactory (
INTERVENTIONAL NEURORADIOLOGY
Clinical significance of post-interventional cerebral hyperdensities after endovascular mechanical thrombectomy in acute ischaemic stroke Omid Nikoubashman & Arno Reich & Mirco Gindullis & Katharina Frohnhofen & Rastislav Pjontek & Marc-Alexander Brockmann & Jörg B. Schulz & Martin Wiesmann
Received: 2 July 2013 / Accepted: 4 November 2013 / Published online: 5 December 2013 # Springer-Verlag Berlin Heidelberg 2013
Abstract Introduction This study aims to investigate the clinical significance of post-interventional cerebral hyperdensities (PCHD) after endovascular mechanical thrombectomy in acute ischaemic stroke. Methods Data of 102 consecutive patients who received postinterventional CT scans within 4.5 h after mechanical thrombectomy were analysed retrospectively. Results Sixty-two of 102 patients (60.8 %) had PCHD on their post-interventional CT scans. The most common site of PCHD was the basal ganglia. PCHD were persisting in 13 of 62 patients (21.0 %), and transient in the remaining 49 patients (79.0 %) within 24 h. Four patients with PCHD and four patients without PCHD suffered from parenchymal haemorrhage. Neither ASA nor Clopidogrel, Tirofiban or rtPA were risk factors for PCHD. Final infarction size was congruent with or bigger than areas of PCHD in 93.3 % of cases in our series. Conclusion PCHD was not a risk factor for parenchymal haemorrhage in our series. The occurrence of PCHD was strongly related to the prior presence of infarction. PCHD was also a strong predictor for final infarction size. Keywords Stroke . Post-interventional CT . Hyperdensity . Haemorrhage . Mechanical recanalisation Electronic supplementary material The online version of this article (doi:10.1007/s00234-013-1303-1) contains supplementary material, which is available to authorized users. O. Nikoubashman : K. Frohnhofen : R. Pjontek : M.2/3 of the vessel territory) [11]. Statistical analyses We applied Chi2 tests, Fisher's exact tests and t tests where adequate. Logistic regression analyses were performed for complex correlations. Results with a p value under 0.05 were considered significant. All statistical analyses were performed using SPSS® 20 software (IBM®, San Jose, California, USA).
Transient PCHD PCHD that became iso- or hypodense to the unaffected contralateral hemisphere within 24 h. Persisting PCHD PCHD that remained hyperdense during at least 24 h. Haemorrhage (according to the ECASS 1 and 2 definition): – – – –
– –
PH: Parenchymal haemorrhage (coagulum) with mass effect PH1: Less that 30 % of the infarcted area with mild spaceoccupying effect PH2: Greater than 30 % of the infarcted area with significant space-occupying effect HI: Haemorrhagic infarction: petechial infarction without space-occupying effect; non-solid and without spaceoccupying effect, respecting borders of grey and white matter [12]. HI1: Small petechiae HI2: More confluent petechiae
Early HI occurring within 36 h after recanalisation was distinguished from delayed HI occurring 36 h after recanalisation [13]. Infarction Infarction diagnosis was based on MRI via diffusion weighted imaging including ADC maps in combination with T2-FLAIR sequences whenever possible. Infarction diagnosis via CT was complicated when final infarction size
Neuroradiology (2014) 56:41–50
could not be assessed in the presence of persisting hyperdensities. We supposed that a complete infarct demarcation can be expected in the following settings: (1) patients without PCHD—CT scan performed at least 12 h after recanalisation; (2) patients with PCHD—CT scan performed at least 12 h after recanalisation if all former hyperdense areas are hypodense. Since it is unknown yet to which extent PCHD correspond to parenchymal infarction, final infarction size was not assessed if PCHD remained isodense to normal parenchyma in follow-up CT scans performed within 24 h after recanalisation. Final infarct size was also not assessed, when PCHD remained hyperdense in the last follow-up CT.
Results Patients One hundred two patients were analysed (49 women, 53 men, n. s.). Mean age of patients was 70.3 years (SD 17.1 years). Men were significantly younger than women (67.8 versus 74.3 years, p =0.036). Interventional treatment Details on interventional treatments are presented in Table 2. Clinical findings Initial median mRS and NIHSS scores of all patients were 5.0 and 14.5, respectively. The mRS score at discharge and the mRS score at 3 months were 4.5 and 4.0, respectively. There was no significant difference between the mRS scores of patients with and without PCHD (administration: p =0.520, discharge: p =0.463, 3 months: p =0.382, twotailed Student's t test).
43
Radiological findings PCHD Sixty-two of 102 patients (60.8 %) had PCHD on their postinterventional CT scans. However, we found PCHD in only 22 of 72 patients (31 %) when we considered only the latest CT performed within 24 h after recanalisation. All visually distinctive hyperdense areas had an increased density of at least 5 HUmax compared to the unaffected contralateral hemisphere and were therefore included in this study. Overall, there were 744 ASPECTS areas in 62 patients. PCHD was present in 206 of 744 ASPECTS areas (27.7 %). Localisations of PCHD were the following (according to ASPECTS): lentiform nucleus (in n = 50 of 62 cases, 80.6 %), M2 area (n =30, 48.4 %), insula (n =30, 48.4 %), caudate nucleus (n =29, 46.8 %), M5 area (n =19, 30.6 %), M1 area (n =11, 17.7 %), M4 area (n =10, 16.1 %), M3 area (n =9, 14.5 %), M6 area (n =8, 12.9 %), A area (n =6, 9.7 %), internal capsule (n =4, 6.5 %). One patient with a foetal posterior cerebral artery had PCHD in the P area. PCHD were persisting in 13 of 62 patients (21.0 %), and transient in the remaining 49 patients (79.0 %) within 24 h. Mean HUmax of all hyperdense areas was 83.7 HU (median, 77.0; ranging from 58 to 152 HU; SD, 22.5). Mean HUmax of areas corresponding to transient hyperdensities was 79.2 HU (median, 74; ranging from 61 to 152 HU; SD, 19.8) and 87.8 HU for areas corresponding to persisting hyperdensities (median, 80; ranging from 72 to 142; SD,19.6). This difference was not statistically significant (p = 0.217, Student's t test). Furthermore, mean HUmax of hyperdense areas of patients with parenchymal haemorrhage was not significantly different from those of patients without parenchymal haemorrhage (p =0.476, Student's t test). Characteristics of patients with and without PCHD are provided in Table 3.
Procedural parameters Haemorrhage Mean time between onset of symptoms until recanalisation or discontinuation of therapy was 325.2 min (median, 303.0; ranging from 120 to 813 min; SD, 134.2). Mean duration of neuroradiological procedure was 131.0 min (median, 115.0; ranging from 30 to 351 min; SD, 74.7). Mean time between recanalisation or discontinuation of therapy until postinterventional CT scan was 76.6 min (median, 70.0; ranging from 27 to 250 min; SD, 34.2). An average of 2.5 recanalisation attempts per patient were performed (median, 2.0; ranging from 1 to 8; SD, 1.7). Recanalisation was successful after one single pass in 39 cases (38.2 %). Stenting of the internal carotid artery was necessary in 23 cases (22.5 %). One stent was placed in the M1 segment of the middle cerebral artery.
Depending on availability of follow-up studies, the occurrence of haemorrhage could be assessed in 88 of 102 patients. This comprises 48 patients with PCHD and 40 patients without PCHD. Parenchymal haemorrhage Four of 88 patients (4 %) suffered from parenchymal haemorrhage with a space occupying effect (ECASS PH2). All four haemorrhagic events occurred within 1 to 4 days after recanalisation. One of these four patients had PCHD (Fig. 1). There was symptomatic mass haemorrhage in two of these four cases—including one patient with PCHD. Haemorrhage in this latter patient occurred 1 day after recanalisation, involved the hyperdense area and was lethal.
44
Neuroradiology (2014) 56:41–50
Four additional patients (4 %) had smaller asymptomatic parenchymal haemorrhage (ECASS PH1) within 4 days after recanalisation. Three of these four patients had PCHD (Fig. 2). PH1 haemorrhage involved hyperdense areas in all 3 patients with PCHD. An overview of all eight patients with PH is provided in Table 4.
Follow-up imaging of these 84 patients was performed after a mean period of 4.2 days after recanalisation (median, 2.2; ranging from 7.0 h to 28.9 days; SD, 4.9 days). Infarct size was assessed via CT in 58 cases (69.0 %) and MRI in 26 cases (31.0 %).
Haemorrhagic infarction Early haemorrhagic infarction occurring within 36 h after recanalisation was present in 2 of 88 patients (2 %). Overall, there was HI in 22 of 88 cases (25.0 %). Complete recanalisation (≥TICI 2b) was significantly associated with the occurrence of HI (p =0.047, two-sided Fisher's exact test).
Predisposing factors for the occurrence of PCHD
Infarction Follow-up imaging suitable for infarction diagnosis was available for 84 patients. This comprises 45 patients with PCHD and 39 patients without PCHD.
Basic statistics indicated that female sex, amount of contrast agent, presence of infarction on intitial CT scan and number of recanalisation attempts may be predisposing factors for the occurrence of PCHD (Table 3). However, logistic regression analyses revealed that only the presence of infarction in the initial CT scan constituted an independent predisposing factor for the occurrence of PCHD (p =0.016) whereas the influence of sex (p =0.205), the amount of contrast agent (p =0.287) and the number of recanalisation attempts (p = 0.261) did not prove significant.
Table 2 Overview of procedural parameters. Number of patients indicated if less than all Vessels
Left/right MCA Terminal ICA with bifurcation Proximal ICA into MCA Proximal ICA and MCA Proximal ICA ACA ACA and MCA Initial degree TICI 0 of occlusion TICI 1 TICI 2a TICI 2ba Final degree of TICI 0 occlusionb TICI 1
rtPA therapy
rtPA dose
TICI 2a TICI 2b TICI 2c TICI 3 Patients with rtPA regardless of application method Patients with intravenously applied rtPA bridging therapy Patients with intraarterially applied rtPA Both intravenous and intraarterial rtPA Mean cumulative rtPA dose regardless of application method Mean dose of intraarterially applied rtPA Mean dose of intravenously applied rtPA
57:45 64 23 8 1 4 1 1 97 (95.1 %) 2 (2 %) 2 (2 %) 1 (1 %) 7 (6.9 %)
(p =0.276, binomial test)
8 (7.8 %) 3 (2.9 %) 11 (10.8 %) 6 (5.9 %) 67 (65.7 %) 74 (72.5 %) 65 (63.72 %) 23 (22.5 %) 14 (13.7 %) 39.3 mg (median, 35.0; ranging from 8 to 98 mg; SD, 20.1). 21.78 mg (median, 15.0; ranging from 5 to 50 mg; SD, 14.5) 37.0 mg (median, 30; ranging from 10 to 98 mg; SD, 20.5).
ICA internal carotid artery, ACA anterior cerbral artery, MCA middle cerebral artery, rtPA recombinant tissue-type plasminogen activator a
Occlusion of the pericallosal artery with severe perfusion deficits in CT perfusion imaging
b
All TICI scores improved after treatment except for seven patients with initial and final TICI 0 occlusions (93.1 %)
Neuroradiology (2014) 56:41–50 Table 3 Overview of patients with and without post-interventional cerebral hyperdensities (PCHD)
Number of patients analysed are indicated in parentheses. p values according to Pearson's Chi2 test, Fisher's exact test and Student's t test PH parenchymal haemorrhage according to ECASS criteria (see above), HI haemorrhagic infarction according to ECASS criteria (see above), GP 2b/3a Glycoprotein 2b/3a * significant p-values
45
PCHD
No PCHD
p value
n (n) Female/male (102) Age (102) Median NIHSS score at admission Median mRS score at admission
62 (60.8 %) 35:27 71.31 years 14.5 5.0
40 (39.2 %) 14:26 70.24 years 15.0 5.0
0.037* 0.034* 0.737 0.428 0.520
Median mRS score at discharge Median mRS score at 3 months Symptom onset—recanalisation (69) Intervention duration (102) Recanalisation—post-interventional CT (102) No. of recanalisation attempts (102) Infaction in initial CT (102) Final TICI score >2a (102) Amount of contrast agent (102) i.v. rtPA (102) i.a. rtPA (102) GP 2b/3a inhibition (102) Infarction >1/3 MCA territory (84) PH (88) PH 1 PH 2 Symptomatic HI (88)
4.5 4.0 339.51 min 137.81 min 72.85 min 2.8 39/62 53/62 238.71 ml 39/62 15/62 19/62 15/45 4/48 3/4 1/4 1/1 12/48
4.5 4.0 301.58 min 115.45 min 75.25 min 2.0 14/40 31/40 206.25 ml 26/40 8/40 11/40 13/39 4/40 1/4 3/4 1/3 10/40
0.463 0.382 0.258 0.182 0.716 0.019* 0.006* 0.420 0.032* 0.830 0.621 0.734 1.000 0.536
Effects of pharmacologic treatment There was no significant correlation between PCHD, pPCHD, PH or HI and treatment with acetylsalicylic acid (ASA), Clopidogrel, recombinant tissue-type plasminogen activator (rtPA) or Tirofiban (Tables 5 and 6).
1.000
Basic statistics indicated that there seemed to be a statistical trend towards a correlation between Tirofiban and persisting PCHD (p =0.054, one-tailed Fischer's exact test). However, regression analysis (forward, stepwise) revealed that the influence of Tirofiban on persisting PCHD was not significant (p =0.421) when statistical analyses were corrected for the actual stenting procedure as a possible time-consuming cofactor (p =0.012) (Nagelkerke's Pseudo R 2 =0.127). Correlations between PCHD and haemorrhage PCHD were not correlated with the occurrence of parenchymal haemorrhage or haemorrhagic infarction (Table 4). Correlations between PCHD and early signs of infarction in initial imaging
Fig. 1 CT scans of a 85-year-old patient (case 5, Table 4) showing large areas of PCHD in the post-interventional CT scan (a), and mass haemorrhage (ECASS PH2) in the follow-up CT scan on the same day (b). Even though this example may suggest otherwise, a large extent of hyperdensities did not prove to correlate significantly with the occurrence of haemorrhage (p =0.853, Student's t test)
Of 1,224 ASPECTS areas (90.4 %) in the initial scans of all 102 patients, 1,106 were normal while infarction was visible in 118 initial ASPECTS areas (9.6 %). In the 102 post-interventional scans, PCHD was found in 70 of 118 initially infarcted ASPECTS areas (59.3 %) and in 136 of 1,106 initially normal areas (12.3 %). Thus, sensitivity and specificity of initially infarcted areas for PCHD were 34.0 and 95.3 %, respectively. The positive predictive value for
46
Neuroradiology (2014) 56:41–50
Fig. 2 Initial CT scan (a), post-interventional CT scan (b) and follow-up T2-FLAIR (c) and T2* (d) MRI in a 64-year-old woman. The initially hypodense lentiform nucleus (a: arrow) is markedly hyperdense in the
post-interventional CT scan (b: arrow). The MRI scan performed 3 days later reveals a small parenchymal haemorrhage within the lentiform nucleus (ECASS PH1) (c and d: arrow)
hypodensities to predict PCHD was 59.3 %. The correlation between initially infarcted areas and the occurrence of PCHD was significant (p 48 h) of cerebral infarction [20]. PCHD and haemorrhagic transformation share the same features as they are mostly limited to grey matter, and are not spaceoccupying. As PCHD are observed immediately after neurointerventional treatment, it appears unlikely that extravasation of blood contributes significantly to the increased density of PCHD. Nevertheless, in principle, conventional CT cannot differentiate whether the hyperdensity in suspected PCHD is caused by contrast agent or extravasated blood [21]. Some authors distinguish between transient and persisting hyperdensities and suggest that transient PCHD correspond to extravasated contrast agent that is washed out in the course of time, whereas persisting PCHD might correspond to blood in the context of petechial bleeding [3, 4, 6]. However, it is conceivable that transient PCHD may also correspond to subtle haemorrhage, when only small and rapidly reabsorbed amounts of blood pass the damaged BBB. Furthermore, it is possible that persisting PCHD correspond to contrast agent that is trapped in infarcted parenchyma and cannot be washed out. Our analysis and data in the literature lack systematic comparisons of post-interventional CT scans and MRI scans that could help distinguishing iodinated contrast agent from blood. In the end, it is important to note that PCHD, regardless of their true nature, do not resemble parenchymal haemorrhage but physiologic haemorrhagic transformation which is associated with a benign natural history [13, 22]. Predictors of PCHD In accordance with the assumed pathomechanism of PCHD as outline above, the occurrence of PCHD was correlated mainly with the presence of infarction in the initial CT scan both in our data and in the literature [5]. Even though it appears reasonable to assume that higher amounts of contrast agent, an increased duration between onset of symptoms and recanalisation, or the application of rtPA increase the likelyhood of PCHD, neither our results nor data in the literature do support this [8, 9]. Prognostic value of PCHD to predict haemorrhage The overall haemorrhage rate of 7.8 % for parenchymal haemorrhage in our series was comparable to haemorrhage rates provided in the literature [23–29].
48
Neuroradiology (2014) 56:41–50
Fig. 3 Initial CT scan (a), post-interventional CT scan (b), and follow-up T2-FLAIR MRI (c) in a 56-year-old man show matching areas of PCHD (b: arrow) and ischaemia (c: arrow) in the right caudate and lentiform nucleus
Our data and the data provided by Parilla et al. do not suggest there is an increased haemorrhage rate in mechanically treated patients with PCHD, regardless whether transient or persisting (Tables 3 and 4) [8]. Some authors have reported that persisting PCHD may be associated with an increased risk for parenchymal haemorrhage and clinical worsening [4, 6]. However, results provided by Nakano et al. as well as our data do not support this hypothesis [3]. None of the eight cases of parenchymal haemorrhage was associated with persisting PCHD. These results do conflict with analyses dealing with patients who were treated via intra-arterial thrombolytic therapy: all authors observed an increased haemorrhage risk for patients with PCHD [1–6]. In this context, results provided by Rouchaud et al., who analysed mechanically treated patients, stand out: the authors report 11 PH2 (28.9 %) and 21 PH1 (55.3 %) bleedings in 38 patients with PCHD on the one hand, and no PH2 and 2 PH1 (8.0 %) bleedings in 25 patients without PCHD. Their results
are highly significant, but it is noteworthy that the indicated overall haemorrhage rate of 53.0 % in their series is exceptionally high [8, 28, 29]. The overall number of analysed patients may still be too small for a definitive statement. Nevertheless, present data may imply that the natural history of PCHD in the context of intra-arterial thrombolysis and PCHD in the context of mechanical recanalisation differ. Present data may imply that high local concentrations of rtPA that are applied during intra-arterial thrombolytic therapy bear an additional risk for haemorrhage [8]. Correlation between PCHD and early signs of infarction in initial imaging One of the main goals of this study was to elucidate the relationship between PCHD and infarction. Yokogami et al. showed that PCHD are likely to appear in infarcted parenchyma. There was also a significant correlation between the
Fig. 4 Post-interventional CT scan (a) and follow-up diffusion-weighted MRI (b) in a 43-year-old man. Infarcted areas (b) exceed areas with PCHD (a) in this case
Neuroradiology (2014) 56:41–50
Fig. 5 Post-interventional CT scan (a) and follow-up diffusion-weighted MRI (b) in a 77-year-old woman. There is PCHD (a: arrow) without corresponding infarction (b: arrow) in the right insula and inferior frontal gyrus
presence of infarction in the initial CT scan and occurrence of PCHD in our series. More specifically, the location of initial infarction predicted the location of PCHD: Prior infarction in the basal ganglia (lentiform nucleus and caudate nucleus) and the surrounding cortex (insula and M1 area) were significantly associated with the occurrence of PCHD in these areas. This close relationship between infarction and PCHD is also expressed in an overall positive predictive value of 59.3 % for prior infarction to predict PCHD. Correlation between PCHD and final infarction in follow-up imaging The overall positive predictive value for PCHD to predict final infarction was 94.8 % in our series. Even though this figure is very high, one would expect a higher positive predictive value given the hypothesis that disruption of the BBB, thus infarction, is postulated in the presence of PCHD. Final infarct demarcation was lacking in three patients, more precisely in 7 of 134 areas with PCHD. Sulcal contrast agent mimicking parenchymal PCHD due to volume effects might be a possible explanation for the discrepancy between PCHD and infarct demarcation in two of these three patients. However, there was a clear discrepancy between PCHD and final infarction in one patient with a follow-up MRI examination (Fig. 5). This finding was unexpected given the hypothesis that disruption of the BBB is needed for the development of PCHD. A possible explanation could be a transiently increased permeability of the BBB for the contrast agent Iopamidol due to transient ischaemia [30]. In summary, an area with PCHD is most certainly infarcted. However, our data suggest that in rare cases PCHD may also occur in the context of transient ischemia. Final infarction size was congruent with, or bigger than, areas of PCHD in all but three cases (93.3 %) in our series (see above). More precisely, infarction size surpassed areas of PCHD in 57.8 % of patients (Fig. 4). The majority of PCHD
49
cases involved the basal ganglia—first and foremost the lentiform nucleus (80.6 %). Consequently, additional infarction was mainly found in additional cortical areas. Furthermore, our results imply that infarction size is likely to surpass areas of PCHD if final recanalisation is unsatisfactory (
